Opposite effects of nefazodone in two human models of anxiety

Rationale and objectives: To explore further the role of serotonin (5-HT) i n anxiety, the effects of the 5-HT reuptake inhibitor and 5-HT-(2A) recepto r antagonist nefazodone (NF) were measured in two human models of anxiety. Methods: Twenty-nine adult healthy volunteers of both sexes underwent condi tioning of skin conductance responses (CSCR) to a tone associated to an ave rsive white noise. Another 34 subjects performed a simulated public speakin g (SPS) task, seemingly related to unconditioned fear. In both tests, subje ctive states were evaluated through the visual analogue mood scale (VAMS) a nd a bodily symptoms scale (BSS). In each experiment subjects were randomly divided into three groups, which received 100 mg NF, 200 mg NF or placebo under double-blind condition. Results: In the CSCR test, NF decreased the n umber of spontaneous fluctuations of skin conductance (F=4.94; dP=2,26; P=0 .015). In addition, the increase in VAMS anxiety factor induced by the cond itioning task was attenuated by NF (F=11.11; df=2,26; P <0.001). In contras t, the rise of VAMS anxiety induced by SPS was enhanced by NF (F=8.01; df=2 ,31; P=0.002). Conclusions: These results indicate that NF decreases condit ioned anxiety, while enhancing unconditioned fear. Since the effects of NF may be due to impairment of 5-HT neurotransmission, consequent to overstimu lation of autosomic 5-HT1A receptors and blockade of post-synaptic 5-HT2A r eceptors, the present results support the hypothesis that 5-HT facilitates conditioned anxiety, which may be related to generalised anxiety disorder, while inhibiting unconditioned fear, supposedly related to panic disorder.